A Study of Anlotinib in Recurrent/Metastatic Head and Neck Adenocarcinomas

Conditions:   Head and Neck Carcinoma;   Adenocarcinoma;   Recurrent Disease;   Distantly Metastatic Malignant Neoplasm
Intervention:   Drug: Anlotinib
Sponsor:   Shanghai Ninth People's Hospital Affiliated to Shanghai Jiao Tong University
Not yet recruiting

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Effectiveness of Manual Therapy vs Exercises With Foam Rolling for Tension Headache

Condition:   Tension-type Headache
Interventions:   Other: Manual Therapy protocol;   Other: Foam Rolling protocol;   Other: Placebo control
Sponsor:   University of Valencia
Recruiting

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Editorial Board

Publication date: August 2018

Source: Autoimmunity Reviews, Volume 17, Issue 8

Author(s):

https://ift.tt/2msDJMY

The pH-altering agent omeprazole affects rate but not the extent of ibrutinib exposure

Abstract

Purpose

This drug-interaction study evaluated the effect of omeprazole, a proton-pump inhibitor, on ibrutinib's pharmacokinetics (PK) in healthy participants.

Methods

This open-label, sequential-design study included 20 healthy adults aged 18–55 years. Ibrutinib (560 mg, single dose) was administered after an overnight fast alone on day 1 and with omeprazole on day 7. Omeprazole (40 mg) alone was administered on days 3–6, 1 h before breakfast; and after an overnight fast on day 7, followed by ibrutinib 2 h later. Blood was sampled on days 1 and 7 for up to 48 h postdose, and the standard PK parameters for ibrutinib and PCI-45227 were summarized using descriptive statistics. The effect of omeprazole on ibrutinib's PK was determined by assessing geometric mean ratios (GMRs) and 90% CIs. Mechanistic modeling was performed using the BTK-receptor occupancy (RO) model.

Results

AUC_48h and AUC_last of ibrutinib plus omeprazole versus ibrutinib alone showed a modest decrease (GMR [90% CI] 98.3% [83.1–116.3] and 92.5% [77.8–109.9], respectively); C_max decreased by 62.5% (GMR [90% CI] 37.5% [26.4–53.4]), with delayed t_max (1−2 h) and terminal half-life unaffected. Mean AUC for PCI-45227 (primary metabolite) was ~ 20% lower with ibrutinib plus omeprazole versus ibrutinib alone. Model predictions showed no impact of decreased C_max on BTK target engagement. No new safety signals were identified with the use of ibrutinib in this study.

Conclusions

The decrease in C_max without a corresponding decrease in AUC by omeprazole was not clinically relevant for ibrutinib's bioavailability. No dose adjustments are recommended during ibrutinib's co-administration with omeprazole or other pH-altering agents.

https://ift.tt/2zUVsGw

Phase II study of pazopanib in combination with paclitaxel in patients with metastatic melanoma

Abstract

Purpose

This phase II study evaluated the safety and clinical activity of pazopanib, a potent and mutlitargeted tyrosine kinase inhibitor (TKI) of vascular endothelial growth factor receptors (VEGFRs)-1, -2 and -3, platelet-derived growth factor receptor (PDGFR)-α and β, and cKit, in combination with metronomic paclitaxel in patients with metastatic melanoma.

Experimental design

Sixty chemotherapy-naive patients received pazopanib at a starting dose of 800 mg daily in combination with metronomic dosing of paclitaxel 80 mg/m² weekly thrice every 4 weeks. The primary endpoint was 6-month progression-free survival (PFS) rate, while secondary endpoints included 1-year overall survival rate, RECIST response rates, progression-free survival rates and median overall survival. Prior BRAF-targeted therapy or checkpoint inhibitors were permitted.

Results

The 6-month PFS rate was 68%, with a 1-year OS rate of 48%. Objective response rate was 37% comprising one complete and 20 partial responses. Stable disease at 8 weeks was noted in 32 patients (55%) with an overall clinical benefit rate of 93%. Six-month median progression-free survival was 8 months and median OS was 12.7 months. The most frequently (> 15%) reported non-hematologic, treatment-related adverse events were fatigue, diarrhea, hypertension, transaminitis and peripheral neuropathy. Treatment-related non-fatal bowel perforation, a known class effect, occurred in one patient. No significant association was noted between plasma levels of pazopanib and response.

Conclusions

The combination of pazopanib and metronomic paclitaxel was well-tolerated, demonstrating significant activity in metastatic melanoma. Further evaluation of this combination is warranted.

https://ift.tt/2uwJNbw

Clinical pharmacokinetics and safety profile of single agent arsenic trioxide by continuous slow-rate infusion in patients with newly diagnosed acute promyelocytic leukemia

Abstract

Purpose

This study evaluated pharmacokinetics (PK) and safety profiles of single agent arsenic trioxide (ATO, As₂O₃) administrated as continuous slow-rate infusion in patients with newly diagnosed acute promyelocytic leukemia.

Patients and methods

Patients received 0.16 mg/kg ATO per day. ATO was given for 40 min infusion on the first day followed by 18–20 h daily at a very slow rate with infusion speed of 8 drips/min. During the first week, plasma samples were collected immediately before next administration on each day, and 0.5, 1, 2, 4, 8, 12 h after administration, at the end of infusion (18 h) on day 7. Total arsenic was determined by ICPMS. Arsenic species, arsenious acid (As^III) and its metabolites, monomethylarsonic acid (MMA^V) and dimethylarsinic acid (DMA^V), were quantified by UHPLC-ICPMS. Safety assessment and PK analysis was conducted.

Results

Hyperleukocytosis occurred in two patients and no severe toxicity was observed. Total arsenic gradually accumulated from 15.84 to 34.12 ng/mL during the first week of therapy. MMA^V/iAs increased and remained stable at value about 0.6 after day 4, while DMA^V/MMA^V declined under 2 after day 4. Compared with 2 h infusion, clearance (CL) of As^III was significantly lower (0.8 ± 0.2 vs. 2.7 ± 1.7 L/kg/h, P = 0.002) while AUC_0–t of As^III was significantly increased (213.9 ± 38.6 vs. 82.6 ± 55.7 L/kg/h, P = 0.028).

Conclusion

Continuous slow-rate ATO infusion provided an alternative administration for ATO therapy with few toxic effects. Degree of methylation from MMA to DMA is inconsistent with that from iAs to MMA. PK of arsenic species is considered important for clinical use of ATO.

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The association of polymorphisms in folate-metabolizing genes with response to adjuvant chemotherapy of colorectal cancer

Abstract

Background

Colorectal cancer (CRC) is one of the major health issues worldwide. 5-Fluorouracil (5-FU) is a cornerstone of chemotherapy for CRC and the major targets of 5-FU are folate-metabolizing enzymes.

Methods

A total of 103 CRC patients with complete clinical data were included in this prospective cohort study. Genotyping was performed using polymerase chain reaction (PCR) followed by sequencing. Using Kaplan–Meier curves, log-rank tests, and Cox proportional hazard models, we evaluated associations between functional polymorphisms in four genes MTHFR (1298A>C and 677C>T), DPYD (496A>G and 85T>C), DHFR 19 bp del, and MTR (2756 A>G) with disease-free survival (DFS).

Results

The minor allele frequencies of MTHFR 1298A>C, MTHFR 677C>T, DPYD 496A>G, DPYD 85T>C, DHFR 19 bp del, and MTR 2756 A>G were 0.364, 0.214, 0.116, 0.209, 0.383, and 0.097, respectively. CRC patients carrying the homozygous GG genotype in DPYD 496A>G had 4.36 times shorter DFS than wild-type AA carriers, (DFS_GG vs _AA: 8.0 ± 4 vs 69.0 ± 10 months; HR 4.36, 95% CI 1.04–18; p = 0.04). Moreover, female carriers of homozygous CC genotype of DPYD 85T>C had shorter DFS compared to either heterozygous or wild-type genotypes, and were 12.7 times shorter than wild-type TT carriers (DFS_{CC vs TT}: 5.0 ± 1.5 vs 42.0 ± 7.6 months; HR 12.7, 95% CI 2.2–71.4; p = 0.004). However, there were no significant associations with the other studied polymorphisms.

Conclusion

Genetic polymorphism in DPYD seems to be associated with DFS in CRC patients receiving an adjuvant regimen of 5-FU/capecitabine-based chemotherapy. Further studies are needed to verify these findings.

https://ift.tt/2A2pQyT

Therapeutic drug monitoring and dose adaptation of cisplatin in a newborn with hepatoblastoma: a case report

Abstract

Purpose

Chemotherapy dosing in neonates represents a major clinical challenge because of a lack of clinical pharmacology information in this patient population. In this study, we investigate the use of cisplatin dose adaptation based on therapeutic drug monitoring in a 2-week-old neonate with localized hepatoblastoma.

Methods

Cisplatin concentrations were determined in plasma and ultrafiltrate samples collected on each of six cycles of a monotherapy regimen, beginning with a dose of 1.6 mg/kg at 16 days of age. Pharmacokinetic data were analyzed to generate clearance (CL) and area under the curve (AUC_0–∞) for each administration. Toxicity and clinical response were monitored.

Results

The first cisplatin dose (1.6 mg/kg) resulted in an AUC_0–∞ of 535 µg/mL · min, was well tolerated and associated with a good response. This AUC was, therefore, considered as an appropriate target for this patient. Increases in cisplatin CL were observed across consecutive treatment cycles, and, therefore, dose was gradually increased to finally reach 2.5 mg/kg on the sixth cycle. Treatment was well tolerated over the six courses and resulted in a good response, with the patient remaining in remission at 15 months. Cisplatin CL was significantly correlated to age (p = 0.013) and weight (p = 0.013).

Conclusions

Our study provides useful data on the pharmacokinetics of cisplatin monotherapy in neonates treated within the first few weeks of life. These data provide a reference point to support clinicians in determining appropriate dosing regimens for neonates and support the implementation of therapeutic drug monitoring in such challenging patients.

https://ift.tt/2uzV9vD

A pharmacodynamic study of sirolimus and metformin in patients with advanced solid tumors

Abstract

Background

Sirolimus is a mammalian target of rapamycin (mTOR) inhibitor. Metformin may potentiate mTOR inhibition by sirolimus while mitigating its adverse effects. We conducted a pilot study to test this hypothesis.

Methods

Patients with advanced solid tumor were treated with sirolimus for 7 days followed by randomization to either sirolimus with metformin (Arm A) or sirolimus (Arm B) until day 21. From day 22 onwards, all patients received sirolimus and metformin. The primary aim was to compare the change in phospho-p70S6K (pp70S6K) in peripheral blood mononuclear cells (PBMC) from day 8 to day 22 using a two-sample t test. Secondary aims were objective response rate, toxicity, and other serum pharmacodynamic biomarkers (e.g., fasting glucose, triglycerides, insulin, C-peptide, IGF-1, IGF-1R, IGF-BP, and leptin).

Results

24 patients were enrolled, with 18 evaluable for the primary endpoint. There was no significant difference in mean change in pp70S6K in arm A vs. arm B (− 0.12 vs. − 0.16; P = 0.64). Similarly, there were no significant differences in other serum pharmacodynamic biomarkers. There were no partial responses. There were no dose-limiting or unexpected toxicities.

Conclusions

Adding metformin to sirolimus, although well tolerated, was not associated with significant changes in pp70S6K in PBMC or other serum pharmacodynamic biomarkers.

Impact

Combining metformin with sirolimus did not improve mTOR inhibition.

https://ift.tt/2A2pNTJ

Relationship of peak serum methotrexate concentration to prognosis and drug tolerance in non-metastatic extremity osteosarcomas

Abstract

Purpose

This study aimed to explore whether peak serum methotrexate concentration (C_max) correlated with adverse events, overall survival (OS) and event-free survival (EFS) in patients with primary extremity osteosarcoma.

Methods

Patients with extremity osteosarcoma who were treated at our center between 2005 and 2015 were retrospectively studied. All the patients were Enneking stage II and had received standard perioperative chemotherapy composed of high-dose methotrexate, doxorubicin, cisplatin and ifosfamide. C_max and treatment-associated toxicities of each cycle were recorded. OS and EFS were estimated and compared by Kaplan–Meier survival analysis, and Cox regression models were performed for univariate comparisons.

Results

In total, 567 patients were followed for an average of 53 months (24–104 months). The estimated 3- and 5-year EFS were 71.7 and 63.1%, and the 3- and 5-year OS were 78.2 and 72.9%, respectively. C_max ranged from 527 to 2495 µmol/L with a mean value of 931 ± 106 µmol/L. No significant differences in EFS and OS (p = 0.18 and p = 0.28) were observed among patients with a mean C_max > 1500, > 1000, > 700 and < 700 µmol/L. However, patients with a mean C_max > 1500 µmol/L had significantly increased rates of grade 3–5 toxicity. In the univariate analysis, C_max was not a prognostic factor for EFS (p = 0.08) or OS (p = 0.16).

Conclusions

C_max did not correlate significantly with the oncologic prognosis of non-metastatic extremity osteosarcoma patients treated by multi-agent chemotherapy; however, C_max correlated closely with toxicities and complications. The persistent inclusion of methotrexate in classical multidisciplinary chemotherapy was questioned and should be examined in future trials.

https://ift.tt/2uvg571

Reply to: Relationship between LAT1 expression and resistance to chemotherapy in pancreatic ductal adenocarcinoma

https://ift.tt/2A2pKav

Over-adherence to capecitabine: a potential safety issue in breast and colorectal cancer patients

Abstract

Purpose

The aim of the OCTO clinical study was to measure patients' adherence to capecitabine-based treatment.

Methods

A cohort of ambulatory patients treated with capecitabine monotherapy for either locally advanced or metastatic, breast or colorectal cancer was monitored for 6 cycles. Adherence was assessed in all patients by self-completed questionnaires on disease, pill-count and pharmacological dosage of FBAL (metabolite of capecitabine); and in half of the cohort by electronic medication event monitoring systems (MEMS™) recording the opening times of the device.

Results

Forty patients were enrolled between November 2008 and September 2011 and treated by capecitabine for an average of 4.75 cycles (range 1–6). Hand-foot syndrome (HFS) was the most frequently reported toxicity (35% patients), and to a lesser extent fatigue and/or asthenia (21%), nausea and/or vomiting (13%) and diarrhea (11%). In the MEMS™ cohort, 20 patients were included. Patients' adherence was excellent with very few missing occasions (23/2272 records). Close analysis of MEMS™ data revealed unexpected medication patterns, such as patients taking extra days of medication beyond planned cycle, patients taking extra doses per day and patients missing a day of dosing and "compensating" by taking extra the following day (N = 7, 18%). A trend was found between over-adherence and high-grade toxicity (grades 3 and/or 4): OR 4.74 [0.65–45.2], p = 0.13 and higher AUC (p = 0.16). There was a trend towards increased AUC of FBAL in over-adherent patients (p = 0.16).

Conclusion

Adherence to oral anticancer chemotherapy was found excellent in this population suggesting over-adherence to capecitabine and potential safety implications for outpatients' drugs.

https://ift.tt/2uwE2Lk

Gemcitabine plus nab-paclitaxel vs. FOLFIRINOX for patients with advanced pancreatic cancer

Abstract

Purpose

New chemotherapies have become available for the treatment of advanced pancreatic cancer and have led to changes in its standard treatments. Since pancreatic cancer is becoming more common as a result of population aging, there is a need for diversification of chemotherapy.

Methods

Between March 2014 and April 2017, FOLFIRINOX (FFX) or gemcitabine plus nab-paclitaxel (G-nab) was used as first-line therapy to treat 27 patients with locally advanced and metastatic pancreatic cancer at our hospital. In this study, we retrospectively evaluated their clinical characteristics, survival outcomes and adverse events.

Results

Twelve of the 27 patients were treated with FFX, and the other 15 patients were treated with G-nab. The disease control rate was 86.7% in the G-nab group and 75% in the FFX group. Median OS time was 8.9 months in the FFX group and 11.8 months in the G-nab group. The 1-year survival rate was 46.6% in the G-nab group and 16.6% in the FFX group. The second-line treatment rate was 40% in the G-nab group and 66.7% in the FFX group. The grade 3–4 neutropenia rate was 20% in the G-nab group and 25% in the FFX group. No patients developed febrile neutropenia, or severe nausea, diarrhea, or anorexia. The peripheral sensory neuropathy rate was 73.3% in the G-nab group and 75% in the FFX group.

Conclusions

Although G-nab and FFX are effective treatments for advanced pancreatic cancer, the G-nab group had a higher 1-year survival rate, and G-nab can be more safely administered to older patients.

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Pulmonary administration of curcumin inhibits B16F10 melanoma lung metastasis and invasion in mice

Abstract

Purpose

Curcumin is expected to have beneficial effects including an anti-cancer effect. However, its lower bioavailability is a critical concern and limits the utility of curcumin in clinical practice. In this study, we investigated whether transpulmonary delivery of curcumin is pharmacologically effective along with improving its bioavailability in mice with lung metastasis.

Methods

C57BL/6J mice were injected with B16F10 melanoma cells via their tail vein and given curcumin by pulmonary administration every other day. The lung tissue of the vehicle-treated mice on day 17 was covered by nodules of metastatic melanoma.

Results

Pulmonary curcumin administration significantly and dose-dependently protected the lung metastasis of melanoma. The phosphorylation of JNK (c-Jun NH2 terminal kinase) and HLJ1 expression levels in the lung metastatic nodules of the melanoma were significantly increased by pulmonary curcumin administration. The anti-metastatic effect of curcumin was blunted in mice injected with HLJ1 knocked-down B16F10 melanoma. Systemic bioavailability after pulmonary administration was 61-times higher than after oral administration. Additionally, the curcumin concentration in the lung tissue was sustained to a high level until 24 h after pulmonary administration.

Conclusions

This study showed the usefulness of curcumin to suppress lung metastasis of melanoma by pulmonary administration, a method that may overcome the low-bioavailability of curcumin.

https://ift.tt/2uBrAJY

Extracellular vesicles and ctDNA in lung cancer: biomarker sources and therapeutic applications

Abstract

Lung cancer is the leading cause of cancer death in the world. Recently, targeted therapy and anti-programmed cell death receptor 1 (PD-1) and anti-programmed cell death ligand 1 (PD-L1) immunotherapy have made great progress in treatment of lung cancer. However, responses to these therapies are variable, influenced by genetic alterations, high microsatellite instability and mismatch repair deficiency. Liquid biopsy of extracellular vesicles and circulating tumor DNA (ctDNA) emerges as a new promising non-invasive means that enables not only biomarker determination, but also continuous monitoring of cancer treatment. Notably, tumor extracellular vesicles play important roles in tumor formation and progression, and also serve as natural carriers for anti-tumor drugs and short-interfering RNA. In this review, we summarize the latest progress in understanding the relationships of extracellular vesicles and ctDNA in cancer biology, diagnosis and drug delivery. In particular, the application of extracellular vesicles and ctDNA in anti-PD-1/PD-L1 immunotherapy is discussed.

https://ift.tt/2zUHp3M

Pharmacodynamic study using FLT PET/CT in advanced solid malignancies treated with a sequential combination of X-82 and docetaxel

Abstract

Background

A sequential approach, synchronizing cell-cycle specific chemotherapy during VEGFR-TKI treatment breaks, may improve the therapeutic index of this combination therapy. In this study we investigate the safety/tolerability and pharmacodynamic effects of docetaxel used in sequential combination with the novel VEGFR-TKI X-82.

Methods

Patients with advanced solid malignancies underwent 21-day treatment cycles with X-82 administered daily on days 1–14, a treatment break on days 15–20, and docetaxel administered on day 21. Randomization was 1:1 to either a low-dose X-82 (200 mg) or high-dose X-82 (400 mg) arm. Patients were scheduled to undergo four 3′-deoxy-3′-¹⁸F-fluorothymidine (FLT) PET/CT scans to assess changes in tumor cell proliferation. PET standardized uptake values (SUV) were summarized for tumors and changes were assessed using mixed effects models.

Results

14 patients were enrolled and treated with median 3.5 cycles (range 0–12). Three patients in the high-dose cohort (50%) and three patients in the low-dose cohort (38%) experienced at least one grade 3 adverse event during the study (infections, cytopenias, electrolyte abnormalities, and vascular complications). Four patients with 13 metastatic tumors underwent FLT PET/CT scanning. During the cycle 1 X-82 exposure period, tumor SUV_max decreased by − 11% (p = 0.04). After administration of docetaxel and the cycle 2 X-82 exposure period, tumor SUV_max decreased − 44% (p = 0.03).

Conclusions

The sequential combination of X-82 and docetaxel was safe and led to diminished FLT uptake. Further, decrease in FLT uptake during cycle 2 (X-82 plus docetaxel) was greater than in cycle 1 (X-82 alone), suggesting sequential chemotherapy enhances the pharmacodynamic effect of therapy.

https://ift.tt/2LtnZVa

Pharmacokinetic and pharmacodynamic bioequivalence study of a pegfilgrastim biosimilar INTP5 in healthy subjects

Abstract

Purpose

This study compared pharmacokinetics, pharmacodynamics, safety and immunogenicity profiles of INTP5 (a potential pegfilgrastim biosimilar) with that of Neulasta^®.

Methods

In this randomised, assessor-blind, crossover study, 344 healthy subjects received single subcutaneous dose of both INTP5 and Neulasta at 3 mg/0.3 ml (n = 172) or 6 mg/0.6 ml (n = 172) dose. The primary endpoints were AUC_0–t, AUC_0–∞ and C_max of pegfilgrastim; and AUEC_0–t and E_max of absolute neutrophil count (ANC).

Results

All 344 subjects dosed were included in the safety and immunogenicity analyses, and 292 subjects in the pharmacokinetic and pharmacodynamic analyses. At 6 mg dose, test to reference ratio (90% CI) of AUC_0–t was 105.65% (99.60–112.06%), AUC_0–∞ was 105.72% (99.55–112.28%) and C_max was 103.62% (98.19–109.35%); while test to reference ratio (95% CIs) of ANC AUEC_0–t was 100.79% (97.75–103.92%) and E_max was 98.70% (95.52–101.98%). Both the primary endpoints met the bioequivalence criteria (CIs within 80–125%). Similarly, at 3 mg dose, these endpoints were within the acceptance range of 80–125%. CD34+ profiles were similar and 95% CIs were within acceptance range at both doses. Adverse events were reported in 54 (15.7%; 8.72% in INTP5 vs. 8.39% in Neulasta) subjects; most events were mild. The incidences of anti-drug antibodies were low and similar between INTP5 and Neulasta and no neutralising antibodies were detected.

Conclusions

Pharmacokinetic and pharmacodynamic bioequivalence was established between INTP5 and Neulasta following 3 and 6 mg doses. Safety and immunogenicity profiles were similar between INTP5 and Neulasta.

https://ift.tt/2LA1sWE

Phase 1/1b dose escalation and expansion study of BEZ235, a dual PI3K/mTOR inhibitor, in patients with advanced solid tumors including patients with advanced breast cancer

Abstract

Purpose

To determine the maximum tolerated dose (MTD) of BEZ235, an oral inhibitor of class I PI3K and mTOR complexes 1 and 2.

Methods

We performed a phase I/Ib, multicenter, open-label study of oral BEZ235 administered in a continuous daily schedule. The study consisted of two parts: dose-escalation part and safety-expansion part. BEZ235 was administered as a single agent to patients with solid tumors or in combination with trastuzumab for HER2+ advanced breast cancer (aBC). Primary end points were MTD, safety, and tolerability. The secondary end point was pharmacokinetics. Other formulations of BEZ235, solid dispersion system (SDS) sachet, and SDS capsules were also assessed.

Results

One hundred and eighty-three patients were enrolled; single-agent BEZ235 was administered as hard gelatin capsule (n = 59), SDS capsules A and B (n = 33), and SDS sachet (n = 61), amongst which SDS sachet was chosen as the preferred formulation. The monotherapy MTD for capsule A and SDS sachet was determined to be 1000 and 1200 mg/day, respectively. Thirty patients with HER2+ aBC received BEZ235 in combination with trastuzumab. The MTD of BEZ235 in combination with trastuzumab was 600 mg/day. A total of four patients (13.3%) achieved partial response across the different groups. Most frequent AEs in single agent and combination cohorts included nausea (80.3 and 93.3%), diarrhea (75.4 and 80.0%), and vomiting (63.9 and 63.3%).

Conclusions

The MTD of BEZ235 as single agent was 1200 and 600 mg/day with trastuzumab. Pharmacokinetic profiles showed low-to-moderate variability at low dose (10 mg) and high variability at high doses (100 mg and above). Gastrointestinal AEs were frequent at high doses.

https://ift.tt/2uAZJcR

Efficacy of capecitabine in patients with locally advanced or metastatic breast cancer with or without prior treatment with fluoropyrimidine: a retrospective study

Abstract

Purpose

We conducted a retrospective study to assess the outcomes of capecitabine for advanced breast cancer (ABC) after perioperative fluoropyrimidines (FPs).

Methods

The charts of patients with ABC who received capecitabine between 2008 and 2016 at the National Cancer Center Hospital (Tokyo, Japan) were reviewed. Progression-free survival (PFS), overall survival (OS), tumor response, and adverse events (AEs) were compared between two groups: an FP group (prior perioperative FP use) and a non-FP group (no prior FP use).

Results

Overall, 288 patients (FP n = 105; non-FP n = 183) were analyzed. The two groups had similar patient characteristics. The FP group had significantly poorer PFS than the non-FP group (multivariate hazard ratio [HR] 1.33; 95% confidence interval [CI] 1.02–1.73; p = 0.036), although the OS did not differ significantly between the groups (multivariate HR 1.00; 95% CI 0.67–1.50; p = 0.994). With different cut-off values (relapse-free interval [RFI] = 3, 4, and 5 years), multivariate HRs for PFS were 1.32–1.67 (short RFI), and 1.00–1.25 (long RFI). A trend for a larger HR in the FP group compared to the non-FP group with short RFI than in that with long RFI was also seen for OS. Response rate (RR) and disease control rate (DCR) did not differ significantly between the groups (RR in FP vs non-FP 13.8 vs 21.0%; p = 0.173; DCR 54.0 vs 59.9%; p = 0.418). No significant difference in AEs existed between the groups.

Conclusions

Extra caution is needed when capecitabine is considered for patients with ABC who used perioperative FP, especially those who had early recurrence.

https://ift.tt/2zVjnFK

Targeting ALK in pediatric RMS does not induce antitumor activity in vivo

Abstract

Purpose

The anaplastic lymphoma kinase (ALK) has been demonstrated to be a valid clinical target in diseases such as anaplastic large cell lymphoma and non-small cell lung cancer. Recent studies have indicated that ALK is overexpressed in pediatric rhabdomyosarcoma (RMS) and hence we hypothesized that this kinase may be a suitable candidate for therapeutic intervention in this tumor.

Methods

We evaluated the expression of ALK in a panel of pediatric RMS cell lines and patient-derived xenografts (PDX), and sensitivity to ALK inhibitors was assessed both in vitro and in vivo.

Results

Essentially, all RMS lines were sensitive to crizotinib, NVP-TAE684 or LDK-378 in vitro, and molecular analyses demonstrated inhibition of RMS cell proliferation following siRNA-mediated reduction of ALK expression. However, in vivo PDX studies using ALK kinase inhibitors demonstrated no antitumor activity when used as single agents or when combined with standard of care therapy (vincristine, actinomycin D and cyclophosphamide). More alarmingly, however, crizotinib actually accelerated the growth of these tumors in vivo.

Conclusions

While ALK appears to be a relevant target in RMS in vitro, targeting this kinase in vivo yields no therapeutic efficacy, warranting extreme caution when considering the use of these agents in pediatric RMS patients.

https://ift.tt/2uBrvpE